Metabolomic Signatures in Doxorubicin-Induced Metabolites Characterization, Metabolic Inhibition, and Signaling Pathway Mechanisms in Colon Cancer HCT116 Cells.

Doxorubicin (DOX) is a chemotherapeutic agent is used for various cancer cells. To characterize the chemical structural components and metabolic inhibition, we applied a DOX to HCT116 colon cancer cells using an independent metabolites profiling approach. Chemical metabolomics has been involved in the new drug delivery systems. Metabolomics profiling of DOX-applied HCT116 colon cancer cellular metabolisms is rare. We used 1H nuclear magnetic resonance (NMR) spectroscopy in this study to clarify how DOX exposure affected HCT116 colon cancer cells. Metabolomics profiling in HCT116 cells detects 50 metabolites. Tracking metabolites can reveal pathway activities. HCT116 colon cancer cells were evenly treated with different concentrations of DOX for 24 h. The endogenous metabolites were identified by comparison with healthy cells. We found that acetate, glucose, glutamate, glutamine, sn-glycero-3-phosphocholine, valine, methionine, and isoleucine were increased. Metabolic expression of alanine, choline, fumarate, taurine, o-phosphocholine, inosine, lysine, and phenylalanine was decreased in HCT116 cancer cells. The metabolic phenotypic expression is markedly altered during a high dose of DOX. It is the first time that there is a metabolite pool and phenotypic expression in colon cancer cells. Targeting the DOX-metabolite axis may be a novel strategy for improving the curative effect of DOX-based therapy for colon cancer cells. These methods facilitate the routine metabolomic analysis of cancer cells.

Phytomedicinal therapeutics for male infertility: critical insights and scientific updates.

Infertility is a significant cause of anxiety, depression, and social stigma among couples and families. In such cases, male reproductive factors contribute widely to the extent of 20-70%. Male infertility is a multifactorial disease with several complications contributing to its diagnosis. Although its management encompasses both modern and traditional medicine arenas, the first line of treatment, adopted by most males, focuses on the reasonably successful medicinal plant-based conventional therapies. Phyto-therapeutics, which relies on active ingredients from traditionally known herbs, influences sexual behavior and male fertility factors. The potency of these phyto-actives depends on their preparation methods and forms of consumption, including decoctions, extracts, semi-purified compounds, etc., as inferred from in vitro and in vivo (laboratory animal models and human) studies. The mechanisms of action therein involve the testosterone pathway for stimulation of spermatogenesis, reduction of oxidative stress, inhibition of inflammation, activation of signaling pathways in the testes [extracellular-regulated kinase (ERK)/protein kinase B(PKB)/transformation of growth factor-beta 1(TGF-ß1)/nuclear factor kappa-light-chain-enhancer of activated B cells NF-kB signaling pathways] and mediation of sexual behavior. This review critically focuses on the medicinal plants and their potent actives, along with the biochemical and molecular mechanisms that modulate vital pathways associated with the successful management of male infertility. Such intrinsic knowledge will significantly further studies on medicinal plants that improve male reproductive health.

Heavy metal and metalloid - induced reproductive toxicity.

Heavy metals and metalloid exposure are among the most common factors responsible for reproductive toxicity in human beings. Several studies have indicated that numerous metals and metalloids can display severe adverse properties on the human reproductive system. Metals like lead, silver, cadmium, uranium, vanadium, and mercury and metalloids like arsenic have been known to induce reproductive toxicity. Moderate to minute quantities of lead may affect several reproductive parameters and even affect semen quality. The ecological and industrial exposures to the various heavy metals and metalloids have disastrous effects on the reproductive system ensuing in infertility. This work emphasizes the mechanism and pathophysiology of the aforementioned heavy metals and metalloids in reproductive toxicity. Additionally, this work aims to cover the classical protective mechanisms of zinc, melatonin, chelation therapy, and other trending methods to prevent heavy metal-induced reproductive toxicity.

Exploring the Pattern of Metabolic Alterations Causing Energy Imbalance via PPARα Dysregulation in Cardiac Muscle During Doxorubicin Treatment.

Cardiotoxicity by anthracycline antineoplastic drug doxorubicin is one of the systemic toxicity of the cardiovascular system. The mechanism responsible for doxorubicin cardiotoxicity and lipid metabolism remains elusive. The current study tested the hypotheses that the role of peroxisome proliferator-activated receptor α (PPARα) in the progress of doxorubicin-induced cardiomyopathy and its mechanism behind lipid metabolism. In the present study, male rats were subjected to intraperitoneal injection (5-week period) of doxorubicin with different dosages such as low dosage (1.5 mg/kg body weight) and high dosage (15 mg/kg body weight) to induce doxorubicin cardiomyopathy. Myocardial PPARα was impaired in both low dosage and high dosage of doxorubicin-treated rats in a dose-dependent manner. The attenuated level of PPARα impairs the expression of the genes involved in mitochondrial transporter, fatty acid transportation, lipolysis, lipid metabolism, and fatty acid oxidation. Moreover, it disturbs the reverse triacylglycerol transporter apolipoprotein B-100 (APOB) in the myocardium. Doxorubicin elevates the circulatory lipid profile and glucose. Further aggravated lipid profile in circulation impedes the metabolism of lipid in cardiac tissue, which causes a lipotoxic condition in the heart and subsequently associated disease for the period of doxorubicin treatment. Elevated lipids in the circulation translocate into the heart dysregulates lipid metabolism in the heart, which causes augmented oxidative stress and necro-apoptosis and mediates lipotoxic conditions. This finding determines the mechanistic role of doxorubicin-disturbed lipid metabolism via PPARα, which leads to cardiac dysfunction.

Increased pro-inflammatory cytokines in ovary and effect of γ-linolenic acid on adipose tissue inflammation in a polycystic ovary syndrome model.

Polycystic Ovary Syndrome (PCOS), a major endocrine disorder, affects the reproductive function of a woman, along with an association with metabolic conditions like insulin resistance and inflammation. The inflammatory nature of PCOS is much debated over, owing to numerous cases of elevation in cytokine levels. Studies have shown the beneficiary effect of Gamma-Linolenic acid (GLA) in reducing inflammation related to many conditions such as atopic dermatitis, rheumatoid arthritis, arterial disease, obesity, and even PCOS. The study aims at assessing the expression of inflammatory cytokines in the ovary and Peri-ovarian adipose tissue (POAT) of the Dehydroepiandrosterone (DHEA) induced PCOS rat model. Further, this study also evaluates the effect of γ-linolenic Acid (GLA) on these cytokines in POAT. Female Wistar rats were subcutaneously injected with 60 mg/kg DHEA daily for 28 days. These PCOS-induced rats were then orally administered with 50 mg/kg GLA for 14 days. The gene expression of cytokines was assessed by Real Time-PCR. The study showed an increase in the expression of cytokines in the ovary and POAT of the DHEA group. This suggests the role of ovarian adipose in adding to the pro-inflammatory state of PCOS. Moreover, the administration of GLA to the PCOS-induced rats resulted in a reduction of cytokine expression from the POAT, indicating that the compound was successful in reducing the associated inflammation. The study throws light on the possibility of using GLA as a supplementary or naturalistic alternative in ameliorating ovarian adipose-associated inflammation that accompanies PCOS.

The effect of γ-linolenic acid on Polycystic Ovary Syndrome associated Focal Segmental Glomerulosclerosis via TGF-ß pathway.

BACKGROUND: In recent years, female infertility from Polycystic Ovary Syndrome (PCOS) has gained scientific interest. PCOS alters the metabolic and endocrine functioning in females. The elevation in androgens can damage the androgen receptors present on the kidney giving rise to renal disorders like Focal Segmental Glomerulosclerosis (FSGS). Transforming Growth Factor Beta (TGF-ß) in the ovary is activated by activin for Follicle Stimulating Hormone (FSH) secretion and in the kidney by thrombospondin 1 (TSP1) for cell growth and apoptosis. Studies show that gamma-linolenic acid (GLA) effectively treats breast cancer, eczema, inflammatory conditions and PCOS. AIM: The study aimed to find out the possibility of FSGS development in PCOS and to understand the effect of GLA on FSGS via the TGF-ß pathway. METHOD: To carry out the study, the dehydroepiandrosterone (DHEA) induced PCOS model was used. Three groups namely vehicle control, DHEA, and DHEA+GLA, were used with six animals in each. TGF-ß1, TGF-ß2, and TSP1 genes were studied using real-time PCR. RESULTS: The study showed an increase in the level of renal fibrosis biomarker, TSP1, in the DHEA group, which was further decreased by an anti-inflammatory agent, GLA. The TGF-ß1 and TGF-ß2 genes associated with the TGF-ß pathway were seen to be increased in DHEA-induced PCOS rats which showed a possible relation between the two conditions. CONCLUSION: The study shows a possible development of renal fibrosis in the DHEA-induced PCOS model. The GLA might act as a ligand to regulate TGF-ß signaling in glomerulosclerosis in a DHEA-induced PCOS model.

New molecular and biochemical insights of doxorubicin-induced hepatotoxicity.

Chemotherapeutic antibiotic doxorubicin belongs to the anthracycline class, slaughters not only the cancer cells but also non-cancerous cells even in the non-targeted organs thereby resulting in the toxicity. The liver is primarily involved in the process of detoxification and this mini-review we focused mainly to investigate the molecular mechanisms heading hepatotoxicity caused due to doxorubicin administration. The alterations in the doxorubicin treated liver tissue include vacuolation of hepatocytes, degeneration of hepatocyte cords, bile duct hyperplasia and focal necrosis. About the literature conducted, hepatotoxicity caused by doxorubicin has been explained by estimating the levels of liver serum biomarkers, ROS production, antioxidant enzymes, lipid peroxidation, and mitochondrial dysfunction. The liver serum biomarkers such as ALT and AST, elated levels of free radicals inducing oxidative stress characterized by a surge in Nrf-2, FOXO-1 and HO-1 genes and diminution of anti-oxidant activity characterized by a decline in SOD, GPx, and CAT genes. The augmented levels of SGOT, SGPT, LDH, creatine kinase, direct and total bilirubin levels also reveal the toxicity in the hepatic tissue due to doxorubicin treatment. The molecular insight of hepatotoxicity is mainly due to the production of ROS, ameliorated oxidative stress and inflammation, deteriorated mitochondrial production and functioning, and enhanced apoptosis. Certain substances such as extracts from medicinal plants, natural products, and chemical substances have been shown to produce an alleviating effect against the doxorubicin-induced hepatotoxicity are also discussed.